C/EBPα in normal and malignant myelopoiesis.
C/EBPα in normal and malignant myelopoiesis.
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DOI：
10.1007/s12185-015-1764-6
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发表时间：
2015-04
影响因子：
2.1
通讯作者：
Friedman AD
中科院分区：
文献类型：
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作者：
Friedman AD
CCAAT/增强子结合蛋白α（C/EBPα）通过其亮氨酸拉链（LZ）结构域二聚化，通过其碱性区结合DNA，并通过N-末端反式激活结构域激活转录。C/EBPα的活性受几种丝氨酸/苏氨酸激酶和类小泛素化的调节，其基因被RUNX 1和其他转录因子激活，其mRNA稳定性被miRNA修饰，其mRNA受到影响AUG选择的翻译控制。除了诱导分化外，C/EBPα还抑制细胞周期进程和凋亡。在造血过程中，C/EBPα水平随着长期干细胞进展为粒细胞-单核细胞祖细胞（GMP）而增加。缺乏C/EBPα会阻止GMP形成，与单细胞生成相比，粒细胞生成需要更高的水平。C/EBPα与AP-1蛋白相互作用，在单细胞生成过程中结合杂交DNA元件，并且C/EBPα诱导Gfi-1、C/EBPε、KLF 5和miR-223能够实现粒细胞生成。CEBPA ORF在约10%的急性髓性白血病（AML）中发生突变，导致N末端截短的C/EBPαp30和C末端符合读框的C/EBPαLZ变体表达，这些变体抑制C/EBPα活性，但在髓样转化过程中也发挥其他作用。在其他AML病例中，RUNX 1突变、CEBPA启动子甲基化、Trib 1或Trib 2介导的C/EBPαp42降解以及导致C/EBPα丝氨酸21磷酸化的信号通路降低了C/EBPα表达或活性。
CCAAT/enhancer binding protein α (C/EBPα) dimerizes via its leucine zipper (LZ) domain to bind DNA via its basic region and activate transcription via N-terminal trans-activation domains. The activity of C/EBPα is modulated by several serine/threonine kinases and via sumoylation, its gene is activated by RUNX1 and additional transcription factors, its mRNA stability is modified by miRNAs, and its mRNA is subject to translation control that affects AUG selection. In addition to inducing differentiation, C/EBPα inhibits cell cycle progression and apoptosis. Within hematopoiesis, C/EBPα levels increase as long-term stem cells progress to granulocyte–monocyte progenitors (GMP). Absence of C/EBPα prevents GMP formation, and higher levels are required for granulopoiesis compared to monopoiesis. C/EBPα interacts with AP-1 proteins to bind hybrid DNA elements during monopoiesis, and induction of Gfi-1, C/EBPε, KLF5, and miR-223 by C/EBPα enables granulopoiesis. The CEBPA ORF is mutated in approximately 10 % of acute myeloid leukemias (AML), leading to expression of N-terminally truncated C/EBPαp30 and C-terminal, in-frame C/EBPαLZ variants, which inhibit C/EBPα activities but also play additional roles during myeloid transformation. RUNX1 mutation, CEBPA promoter methylation, Trib1 or Trib2-mediated C/EBPαp42 degradation, and signaling pathways leading to C/EBPα serine 21 phosphorylation reduce C/EBPα expression or activity in additional AML cases.